Halo-substituted hydroxybenzyl-amines as secretolytic agents

ABSTRACT

Compounds of the formula ##STR1## wherein X is chlorine or bromine; 
     R 1  is hydrogen, chlorine or bromine; 
     R 2  is isopropyl; tert.butyl; tert.pentyl; mono-, di- or tri-hydroxy-substituted branched alkyl of 3 to 5 carbon atoms; cyclohexyl; or hydroxycyclohexyl; and 
     R 3  is alkyl of 1 to 4 carbon atoms or, when R 2  is other than cyclohexyl, also hydrogen; 
     And non-toxic, pharmacologically acceptable acid addition salts thereof; the compounds as well as their salts are useful as secretolytics, antitussives, anti-ulcerogenics and stimulants for the production of the surfactant or anti-atelectasis factor of the alveoli.

This is a continuation-in-part of copending applications Ser. No.408,071 filed Oct. 19, 1973, and Ser. No. 561,223 filed Mar. 24, 1975,both now abandoned.

This invention relates to novel halo-substituted hydroxybenzylamines andacid addition salts thereof, as well as to various methods of preparingthese compounds.

More particularly, the present invention relates to a novel class ofcompounds represented by the formula ##STR2## wherein X is chlorine orbromine;

R₁ is hydrogen, chlorine or bromine;

R₂ is isopropyl; tert.butyl; tert.pentyl; mono-, di- ortri-hydroxy-substituted branched alkyl of 3 to 5 carbon atoms;cyclohexyl; or hydroxycyclohexyl; and

R₃ is alkyl of 1 to 4 carbon atoms or, when R₂ is other than cyclohexyl,also hydrogen;

And non-toxic, pharmacologically acceptable acid addition salts thereof.

The compounds embraced by formula I may be prepared by various methodsinvolving known chemical principles, among which the following haveproved to be particularly convenient and efficient:

Method A

By reaction of a compound of the formula ##STR3## wherein R₁ and X havethe same meanings as in formula I and R₄ is hydroxyl, chlorine, bromine,iodine, acyloxy, sulfonyloxy, alkoxy, aryloxy or aralkoxy,

With an amine of the formula ##STR4## wherein R₂ and R₃ have the samemeanings as in formula I.

The reaction is appropriately performed in a solvent, such as acetone,carbon tetrachloride, chloroform, ethanol, tetrahydrofuran, benzene,toluene, dioxane or tetrahydronaphthalene, or in an excess of the aminereactant of the formula III and, depending on the reactivity of R₄, attemperatures between -70° and 200° C. The reaction may, however, becarried out as well in the absence of a solvent.

If R₄ is halogen, the reaction is preferably carried out at temperaturesbetween 0° and 150° C, for example at the boiling point of theparticular solvent which is used, and appropriately in the presence of ahydrogenhalide-binding agent, for instance an inorganic base, such assodium carbonate or sodium hydroxide, or in the presence of an ionexchanger or a tertiary organic base, such as triethylamine or pyridine.The latter may serve as a solvent at the same time.

If R₄ is sulfonyloxy, for instance 4-methyl-phenyl-sulfonyloxy, thereaction is preferably performed at temperatures between -70° and 50° C.

If R₄ is acyloxy, for example acetoxy, benzoyloxy, alkoxy, aryloxy oraralkoxy, the reaction is optionally carried out in the presence of anacid catalyst, such as ammonium chloride, preferably at temperaturesbetween 0° and 200° C.

If R₄ is hydroxyl, the reaction is optionally performed in the presenceof an acid catalyst, such as hydrobromic acid, p-toluene-sulfonic acidor butyric acid, or optionally in the presence of an alkaline catalyst,such as potassium hydroxide or magnesium oxide, preferably attemperatures between 120° and 180° C. The reaction may, however, beperformed as well without any solvent.

Method B

By reaction of an aldehyde of the formula ##STR5## wherein R₁ and X havethe same meanings as in formula I, with an amine of the formula ##STR6##wherein R₂ and R₃ have the same meanings as in formula I, or with thecorresponding formamide in the presence of formic acid.

The reductive amination is preferably carried out at temperaturesbetween 50° and 250° C, optionally in a solvent and optionally whiledistilling off at the same time the water that is formed. It is ofspecial advantage, however, to use the amine of the formula III and/orthe formic acid during the reaction as a solvent at the same time. If R₃is hydrogen in a compound of the formula III, the reaction mixtureobtained is refluxed after the reaction with a dilute acid, such as 2 Nhydrochloric acid.

Method C

For the preparation of a compound of the formula I wherein R₃ ishydrogen:

By reduction of a compound of the formula ##STR7## or of a compound ofthe formula ##STR8## wherein R₁, R₂ and X have the same meanings as informula I, Z is cyclohexylidene optionally substituted by hydroxyl or byalkyl of 1 to 4 carbon atoms or branched alkylidene of 3 to 5 carbonatoms, and R₅ is hydrogen or organic acyl.

If R₅ is hydrogen, the reduction is appropriately carried out withcatalytically activated hydrogen, for example, with hydrogen in thepresence of Raney nickel or Raney cobalt; or with nascent hydrogengenerated, for instance, with activated metallic aluminum and water; orwith sodium amalgam and ethanol; or with zinc and hydrochloric acid; orthe reduction is carried out with a complex metal hydride -- which is ofspecial advantage --, such as lithium aluminum hydride or sodiumborohydride, in the presence of an appropriate solvent, such asmethanol, ethanol, ethanol/water, tetrahydrofuran, dioxane,dioxane/water, pyridine or ether, at temperatures up to the boilingpoint of the solvent used, for instance between -50° and 100° C.

If, in a compound of the formula V or Va, R₅ is organic acyl, the latteris split off during the reduction with nascent hydrogen or with acomplex metal hydride.

Method D

For the preparation of a compound of the formula I wherein R₃ is otherthan hydrogen, and R₂ and R₃ are not substituted by hydroxyl.

By alkylation of a compound of the formula ##STR9## wherein R₁ and Xhave the same meanings as in formula I and R₂ ' is hydrogen or alkyl of1 to 4 carbon atoms and has the same meanings as R₂ in formula I exceptbranched alkyl of 3 to 5 carbon atoms substituted with 1 to 3 hydroxyls,and hydroxycyclohexyl, with a compound of the formula

    R.sub.3 ' -- W                                             (VII)

wherein R₃ ' is branched alkyl of 3 to 5 carbon atoms, cyclohexyl, orhas the same meanings as R₃ in formula I except hydrogen and W ishalogen or sulfonyl.

The reaction is advantageously carried out in the presence of a solventsuch as methanol, dioxane or dimethylformamide, appropriately attemperatures between -20° and 150° C, preferably, however, at theboiling point of the solvent used.

A methylation may also be carried out with formaldehyde in the presenceof formic acid at elevated temperatures, for instance at the boilingpoint of the reaction mixture.

Method E

By reaction of a phenol of the formula ##STR10## wherein R₁ and X havethe same meanings as in formula I, the X substituent being in the2-position of the compound of the formula VIII, with formaldehyde orparaformaldehyde and an amine of the formula ##STR11## wherein R₂ and R₃have the same meanings as in formula I.

The reaction is advantageously carried out in the presence of a solventsuch as water, methanol, ethanol or dioxane, at temperatures between 0°and 100° C, preferably, however, at the boiling point of the particularsolvent which is used.

The reaction may also be carried out in such a way that a compound ofthe formula ##STR12## wherein R₂ and R₃ have the same meanings as informula I and A is lower alkyl, optionally formed in situ, is reactedwith a compound of the formula VIII.

Method F

By halogenation of a compound of the formula ##STR13## wherein R₁, R₂and R₃ have the same meanings as in formula I.

The halogenation is performed with a halogenating agent, for example,with chlorine, bromine, iodobenzene dichloride or tribromophenolbromine,preferably in the presence of a solvent, for instance in 50-100% aceticacid, in methylene chloride or in tetrahydrofuran in the presence of atertiary organic base, and appropriately at temperatures between -20°and 50° C. Per mol of a compound of the formula IX, used as a base or asalt as well, for example, as hydrochloride, appropriately 1 or 2 molsof a halogenating agent or a slight excess are used. If a hydrohalicacid salt is formed during the reaction it may be isolated as such ormay, if desired, be further purified via the base.

The compounds of formulas II through IX used as starting materials inMethods A through F are either known from the literature or may beprepared according to processes described in the literature.

The benzyl halides of the formula II, for example, may be prepared fromthe corresponding toluene derivates by reaction withN-bromo-succinimide, or with halogen under ultra-violet radiation.

A benzyl alcohol derivative of the formula II is obtained, for instance,by reaction of a corresponding benzyl alcohol with a corresponding acidin the presence of hydrochloric acid, or by reaction of a correspondingbenzyl halide with a corresponding alcohol in the presence of bariumcarbonate. A benzyl alcohol of the formula II is prepared byhalogenation of a corresponding benzyl alcohol.

The aldehydes of the formula IV are obtained, for example, byhalogenation of the corresponding benzaldehydes, and the imines of theformulas V and Va are obtained from the corresponding primary amines andthe corresponding carbonyl compounds. By reduction, for example withsodium boron hydride, of a compound of the formulas V or Va thusobtained, a compound of the formula VI is prepared.

The benzylamines of formula IX are prepared, for instance, by reactionof the corresponding benzyl halides with the corresponding amines.

Since the compounds embraced by formula I are bases, they form acidaddition salts with inorganic or organic acids, and may, if desired, beconverted into such salts by conventional methods. Examples ofnon-toxic, pharmacologically acceptable acid addition salts are thoseformed with hydrochloric acid, phosphoric acid, hydrobromic acid,sulfuric acid, lactic acid, tartaric acid, maleic acid,8-chlorotheophylline or the like.

The following examples illustrate the present invention and will enableothers skilled in the art to understand it more completely. It should beunderstood, however, that the invention is not limited solely to theparticular examples given below.

EXAMPLE 1 N-Ethyl-N-cyclohexyl-(3,5-dibromo-2-hydroxy)-benzylamine andits hydrochloride by method A

17 gm of 3,5-dibromo-2-hydroxy-benzylbromide and 12.7 gm ofN-ethyl-N-cyclohexylamine were heated for 3 hours while refluxing in 150ml of ethanol. Subsequently the reaction mixture was evaporated todryness. The residue was shaken with 150 ml of chloroform and 200 ml ofwater. The chloroform layer was separated, filtered and evaporated todryness. The residue was dissolved in ethanol and acidified withethanolic hydrochloric acid, whereuponN-ethyl-N-cyclohexyl-(3,5-dibromo-2-hydroxy)-benzylamine hydrochloride,m.p. 193°-194° C (decomp.), of the formula ##STR14## crystallized out.

EXAMPLE 2 N-Methyl-N-cyclohexyl-(3,5-dibromo-2-hydroxy)-benzylamine andits hydrochloride by method B

21 gm of 3,5-dibromo-salicylaldehyde, 56.5 gm ofN-methyl-N-cyclohexylamine and 23 gm of formic acid were heated for 6hours to 70°-80° C. After cooling, the reaction product was shaken withchloroform and dilute ammonia. The chloroform layer was separated andevaporated to dryness. The residue was purified by means ofchromatography over 800 gm of silicagel with ethyl acetate/chloroform(1:1). After 0.5 liter of first runnings, the other 0.5 liter wasgathered and evaporated to dryness. The residue was dissolved in 50 mlof ethanol and acidified with ethanolic hydrochloric acid. TheN-methyl-N-cyclohexyl-(3,5-dibromo-2-hydroxy)-benzylamine hydrochloride,m.p. 189°-181° C (decomp.), of the formula ##STR15## crystallized out.

EXAMPLE 3N-(Cis-3'-hydroxy-cyclohexyl)-3,5-dibromo-4-hydroxy-benzylamine and itshydrochloride by method C

19 gm of N-(3,5-dibromo-4-hydroxy-benzylidene)-cis-3-amino-cyclohexanol(m.p. 231°-233° C, decomp.) were suspended in 0.5 liter of ethanol andmixed with 2 gm of sodium boron hydride. The mixture was stirred for 1.5hours at room temperature. Subsequently 200 ml of 2 N sodium hydroxidesolution were added to the mixture and the ethanol was distilled off invacuo. The remaining solution was mixed with ammonium chloride. In doingso a crystalline precipitate was obtained. The latter was sucked off,washed with water, and dissolved in 100 ml of 2 N hydrochloric acidwhile heating. After a short timeN-(cis-3'-hydroxy-cyclohexyl)-3,5-dibromo-4-hydroxy-benzylaminehydrochloride, m.p. 216°-218° C (decomp.), of the formula ##STR16##crystallized out and was then sucked off and washed with acetone.

EXAMPLE 4 N-Methyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine andits hydrochloride by method D

7.2 gm of N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine were dissolvedin 20 ml of formic acid and mixed with 2 ml of 40% formaldehyde. Thesolution was heated for 3 hours over the boiling water bath,subsequently diluted with water and made alkaline with concentratedammonia. The precipitated base was sucked off, washed with water, andN-methyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine hydrochloride,m.p. 168°-170° C (decomp.), of the formula ##STR17## was crystallizedfrom ethanol and ethanolic hydrochloric acid by the addition of a smallquantity of ether.

EXAMPLE 5

Using a procedure analogous to that described in Example 1,N-(trans-4'-hydroxy-cyclohexyl)-3,5-dibromo-2-hydroxy-benzylamine andits hydrochloride, m.p. 212°-218° C (decomp.), of the formula ##STR18##were prepared from 3,5-dibromo-2-hydroxy-benzyl bromide andtrans-4-amino-cyclohexanol.

EXAMPLE 6

Using a procedure analogous to that described in Example 1,N-(cis-3'-hydroxy-cyclohexyl)-3,5-dibromo-2-hydroxy-benzylamine and itshydrochloride, m.p. 128°-136° C (decomp.), were prepared from3,5-dibromo-2-hydroxy-benzyl bromide and cis-3-amino-cyclohexanol.

EXAMPLE 7

Using a procedure analogous to that described in Example 1,N-(trans-3'-hydroxy-cyclohexyl)-3,5-dibromo-2-hydroxy-benzylamine andits hydrochloride, m.p. 203°-204.5° C (decomp.), were prepared from3,5-dibromo-2-hydroxy-benzyl bromide and trans-3-amino-cyclohexanol.

EXAMPLE 8

Using a procedure analogous to that described in Example 2,N-methyl-N-(trans-4'-hydroxy-cyclohexyl)-3,5-dibromo-2-hydroxy-benzylamineand its hydrochloride, m.p. 120° C (decomp.), were prepared from3,5-dibromo-salicylaldehyde, trans-4-methyl-amino-cyclohexanol andformic acid.

EXAMPLE 9

Using a procedure analogous to that described in Example 1,N-methyl-N-(cis-3'-hydroxy-cyclohexyl)-3,5-dibromo-2-hydroxy-benzylamineand its hydrochloride, m.p. 80°-83° C (decomp.), were prepared from3,5-dibromo-2-hydroxy-benzyl bromide andcis-3-methyl-amino-cyclohexanol.

EXAMPLE 10

Using a procedure analogous to that described in Example 1,N-ethyl-N-(trans-4'-hydroxy-cyclohexyl)-3,5-dibromo-2-hydroxy-benzylamineand its hydrochloride, as ethanolate, m.p. 135°-137° C (decomp.), wereprepared from 3,5-dibromo-2-hydroxy-benzyl bromide andtrans-4-ethylamino-cyclohexanol.

EXAMPLE 11

Using a procedure analogous to that described in Example 1,N-propyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine and itshydrochloride, m.p. 178°-180° C (decomp.), were prepared from3,5-dibromo-2-hydroxy-benzyl bromide and N-propyl-cyclohexylamine.

EXAMPLE 12

Using a procedure analogous to that described in Example 1,N-isopropyl-N-cyclohexyl-3,5-dibromo-2-hydroxybenzylamine, m.p.108°-110° C, was prepared from 3,5-dibromo-2-hydroxy-benzyl bromide andN-isopropyl-cyclohexylamine.

EXAMPLE 13

Using a procedure analogous to that described in Example 1,N-(trans-4'-hydroxy-cyclohexyl)-3,5-dibromo-4-hydroxy-benzylamine andits hydrochloride, m.p. 220°-225° C (decomp.), of the formula ##STR19##were prepared from 3,5-dibromo-4-hydroxy-benzyl bromide andtrans-4-amino-cyclohexanol.

EXAMPLE 14

Using a procedure analogous to that described in Example 1,N-(trans-3'-hydroxy-cyclohexyl)-3,5-dibromo-4-hydroxy-benzylamine andits hydrochloride, m.p. 215°-215.5° C (decomp.), were prepared from3,5-dibromo-4-hydroxy-benzyl bromide and trans-3-amino-cyclohexanol.

EXAMPLE 15

Using a procedure analogous to that described in Example 1,N-methyl-N-(trans-4'-hydroxy-cyclohexyl)-3,5-dibromo-4-hydroxy-benzylamineand its hydrochloride, m.p. 160°-162° C (decomp.), were prepared from3,5-dibromo-4-hydroxy-benzyl bromide andtrans-4-methylamino-cyclohexanol.

EXAMPLE 16

Using a procedure analogous to that described in Example 1,N-methyl-N-(cis-3'-hydroxy-cyclohexyl)-3,5-dibromo-4-hydroxy-benzylamine,m.p. 133°-136° C, was prepared from 3,5-dibromo-4-hydroxy-benzyl bromideand cis-3-methylaminocyclohexanol.

EXAMPLE 17

Using a procedure analogous to that described in Example 1,N-ethyl-N-(trans-4'-hydroxy-cyclohexyl)-3,5-dibromo-4-hydroxy-benzylamineand its hydrochloride, m.p. 176°-178° C (decomp.), were prepared from3,5-dibromo-4-hydroxy-benzyl bromide andtrans-4-ethylamino-cyclohexanol.

EXAMPLE 18

Using a procedure analogous to that described in Example 1,N-ethyl-N-(cis-3'-hydroxy-cyclohexyl)-3,5-dibromo-4-hydroxy-benzylamine,m.p. 134°-136° C (decomp.), was prepared from3,5-dibromo-4-hydroxy-benzyl bromide and cis-3-ethylamino-cyclohexanol.

EXAMPLE 19

Using a procedure analogous to that described in Example 1,N-propyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine, m.p. 115°-116°C (decomp.), was prepared from 3,5-dibromo-4-hydroxy-benzyl bromide andN-propyl-cyclohexylamine.

EXAMPLE 20

Using a procedure analogous to that described in Example 1,N-methyl-N-cyclohexyl-3,5-dichloro-2-hydroxy-benzylamine and itshydrochloride, m.p. 174°-178° C of the formula ##STR20## were preparedfrom 3,5-dichloro-2-hydroxy-benzyl bromide and N-methyl-cyclohexylamine.

EXAMPLE 21

Using a procedure analogous to that described in Example 1,N-ethyl-N-cyclohexyl-3,5-dichloro-2-hydroxy-benzylamine and itshydrochloride, m.p. 185°-188° C (decomp.), were prepared from3,5-dichloro-2-hydroxy-benzyl bromide and N-ethyl-cyclohexylamine.

EXAMPLE 22

Using a procedure analogous to that described in Example 1,N-ethyl-N-(trans-4'-hydroxy-cyclohexyl)-3,5-dichloro-2-hydroxy-benzylamineand its hydrochloride, m.p. 147°-152° C, of the formula ##STR21## wereprepared from 3,5-dichloro-2-hydroxy-benzyl bromide andtrans-4-ethylamino-cyclohexanol.

EXAMPLE 23

Using a procedure analogous to that described in Example 1,N-propyl-N-cyclohexyl-3,5-dichloro-2-hydroxy-benzylamine and itshydrochloride, m.p. 168°-170° C were prepared from3,5-dichloro-2-hydroxy-benzyl bromide and N-propylcyclohexylamine.

EXAMPLE 24

Using a procedure analogous to that described in Example 1,N-isopropyl-N-cyclohexyl-3,5-dichloro-2-hydroxy-benzylamine, m.p.86°-89° C, was prepared from 3,5-dichloro-2-hydroxy-benzyl bromide andN-isopropyl-cyclohexylamine.

EXAMPLE 25

Using a procedure analogous to that described in Example 1,N-ethyl-N-cyclohexyl-3,5-dichloro-4-hydroxy-benzylamine and itshydrochloride, m.p. 190°-191° C (decomp.), of the formula ##STR22## wereprepared from 3,5-dichloro-4-hydroxy-benzyl bromide andN-ethyl-cyclohexylamine.

EXAMPLE 26

Using a procedure analogous to that described in Example 1,N-ethyl-N-cyclohexyl-3-bromo-5-chloro-2-hydroxy-benzylamine and itshydrochloride, m.p. 194°-197° C (decomp.), of the formula ##STR23## wereprepared from 3-bromo-5-chloro-2-hydroxy-benzyl bromide andN-ethyl-cyclohexylamine.

EXAMPLE 27

Using a procedure analogous to that described in Example 1,N-ethyl-N-cyclohexyl-5-bromo-3-chloro-2-hydroxy-benzylamine and itshydrochloride, m.p. 188°-191° C (decomp.), were prepared from5-bromo-3-chloro-2-hydroxy-benzyl bromide and N-ethyl-cyclohexylamine.

EXAMPLE 28

Using a procedure analogous to that described in Example 2,N-methyl-N-cyclohexyl-(5-bromo-2-hydroxy)-benzylamine and itshydrochloride, m.p. 194°-197° C, of the formula ##STR24## were preparedfrom 5-bromo-salicylaldehyde, N-methyl-cyclohexylamine and formic acid.

EXAMPLE 29

Using a procedure analogous to that described in Example 2,N-ethyl-N-cyclohexyl-(5-bromo-2-hydroxy)-benzylamine and itshydrochloride, m.p. 175°-178° C, were prepared from5-bromo-salicylaldehyde, N-ethyl-cyclohexylamine and formic acid.

EXAMPLE 30

Using a procedure analogous to that described in Example 2,N-ethyl-N-(trans-4'-hydroxy-cyclohexyl)-5-bromo-2-hydroxy-benzylamineand its hydrochloride, m.p. 190°-193° C (decomp.), of the formula##STR25## were prepared from 5-bromo-salicylaldehyde,trans-4-ethylaminocyclohexanol and formic acid.

EXAMPLE 31

Using a procedure analogous to that described in Example 2,N-propyl-N-cyclohexyl-5-bromo-2-hydroxy-benzylamine and itshydrochloride, m.p. 166°-169° C (decomp.), were prepared from5-bromo-salicylaldehyde, N-propyl-cyclohexylamine and formic acid.

EXAMPLE 32

Using a procedure analogous to that described in Example 2,N-isopropyl-N-cyclohexyl-5-bromo-2-hydroxy-benzylamine, m.p. 90°-93° C,was prepared from 5-bromo-salicylaldehyde, N-isopropyl-cyclohexylamineand formic acid.

EXAMPLE 33

Using a procedure analogous to that described in Example 2,N-methyl-N-cyclohexyl-5-chloro-2-hydroxy-benzylamine and itshydrochloride, m.p. 194°-198° C, were prepared from5-chloro-salicylaldehyde, N-methyl-cyclohexylamine and formic acid.

EXAMPLE 34

Using a procedure analogous to that described in Example 2,N-ethyl-N-cyclohexyl-5-chloro-2-hydroxy-benzylamine and itshydrochloride, m.p. 169°-171° C, were prepared from5-chloro-salicylaldehyde, N-ethyl-cyclohexylamine and formic acid.

EXAMPLE 35

Using a procedure analogous to that described in Example 2,N-propyl-N-cyclohexyl-5-chloro-2-hydroxy-benzylamine and itshydrochloride, m.p. 140°-142° C, were prepared from5-chloro-salicylaldehyde, N-propyl-cyclohexylamine and formic acid.

EXAMPLE 36

Using a procedure analogous to that described in Example 2,N-isopropyl-N-cyclohexyl-5-chloro-2-hydroxy-benzylamine, m.p. 85°-88° C,was prepared from 5-chloro-salicylaldehyde, N-isopropyl-cyclohexylamineand formic acid.

EXAMPLE 37

Using a procedure analogous to that described in Example 1,N-methyl-N-cyclohexyl-3-bromo-4-hydroxy-benzylamine and itshydrochloride, m.p. 165°-169° C (decomp.), of the formula ##STR26## wereprepared from 3-bromo-4-hydroxy-benzyl bromide andN-methyl-cyclohexylamine.

EXAMPLE 38

Using a procedure analogous to that described in Example 1,N-ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine and itshydrochloride, m.p. 180°-181° C (decomp.), were prepared from3,5-dibromo-4-hydroxy-benzyl bromide and N-ethyl-cyclohexylamine.

EXAMPLE 39 N-Ethyl-N-cyclohexyl-2-bromo-5-hydroxy-benzylamine and itshydrochloride by method A

54 gm of 2-bromo-5-hydroxy-benzyl bromide in 800 ml ofcarbontetrachloride were mixed with 51 gm of N-ethylcyclohexylamine andrefluxed for 1 hour. Subsequently, the reaction mixture was extractedtwice with water, and the organic phase was dried with sodium sulfateand evaporated. The residue was purified by means of columnchromatography over silicagel with ethyl acetate as the eluant. Thecrude base was dissolved in ethyl acetate and acidified with absoluteethanolic hydrochloric acid, whereuponN-ethyl-N-cyclohexyl-2-bromo-5-hydroxy-benzylamine hydrochloride, m.p.183°-188° C (decomp.), of the formula ##STR27## crystallized out.

EXAMPLE 40N-(Trans-4'-hydroxy-cyclohexyl)-2,4-dibromo-5-hydroxy-benzylamine andits hydrochloride by method C

3.5 gm ofN-(2,4-dibromo-5-hydroxy-benzylidene)-trans-4-amino-cyclohexanol in 70ml of ethanol were mixed dropwise with a solution of 0.4 gm of sodiumborohydride in 5 ml of water while stirring. After stirring for 1 hour,10 ml of 2 N sodium hydroxide solution and 30 ml of water were added tothe solution, which was then evaporated to half its volume.Subsequently, the solution was admixed with a saturated aqueous solutionof ammonium chloride, thus precipitatingN-(trans-4'-hydroxy-cyclohexyl)-2,4-dibromo-5-hydroxy-benzylamine. Theprecipitate was sucked off, suspended in acetone, warmed and acidifiedwith absolute ethanolic hydrochloric acid, whereupon the base dissolvedand the hydrochloride, m.p. 268°-270° C (decomp.), of the formula##STR28## crystallized out immediately.

EXAMPLE 41 N-Methyl-N-cyclohexyl-3-bromo-5-chloro-4-hydroxy-benzylamineby method F

3.6 gm of N-methyl-N-cyclohexyl-3-bromo-4-hydroxy-benzylaminehydrochloride were dissolved in 50 ml of 90% acetic acid and admixedwith a solution of 0.75 gm of chlorine in 15 ml of glacial acetic acidwhile cooling with ice water. After stirring for a short time, thesolution was poured into a mixture of ice and 10 N sodium hydroxidesolution and extracted three times with methylene chloride. The organicphase was evaporated to dryness. The residue was purified by means ofcolumn chromatography over silicagel with ethyl acetate as the eluant,yielding N-methyl-N-cyclohexyl-3-bromo-5-chloro-4-hydroxy-benzylamine,m.p. 136°-138° C, of the formula ##STR29## after recrystallization fromethanol/ether.

EXAMPLE 42 N-Ethyl-N-cyclohexyl-5-bromo-3-chloro-4-hydroxy-benzylamineand its hydrochloride by method F

2.3 gm of N-ethyl-N-cyclohexyl-3-chloro-4-hydroxy-benzylamine weredissolved in 20 ml of 75% acetic acid and admixed dropwise, whilestirring, with 1.6 gm of bromine. The solution was diluted with water,made alkaline with aqueous concentrated ammonia, and extracted twicewith chloroform. The organic phase was dried over sodium sulfate andevaporated. The residue was dissolved in absolute ethanol and acidifiedwith absolute ethanolic hydrochloric acid. Upon addition of ether,N-ethyl-N-cyclohexyl-5-bromo-3-chloro-4-hydroxy-benzylaminehydrochloride, m.p. 165°-168° C (decomp.), of the formula ##STR30##crystallized out.

EXAMPLE 43 N-Ethyl-N-cyclohexyl-3-chloro-2-hydroxy-benzylamine and itshydrochloride by method E

13 gm of N-ethyl-cyclohexylamine and 3 gm of paraformaldehyde weredissolved, while heating, in 100 ml of ethanol, then cooled, admixedwith 13 gm of 2-chloro-phenol, left standing for 1.5 hours at roomtemperature and finally refluxed for 3 hours. Subsequently, the solutionwas evaporated, and the residue was purified with ethyl acetate on acolumn of silicagel. The crude base was dissolved in absolute ethanoland acidified with absolute ethanolic hydrochloric acid.N-ethyl-N-cyclohexyl-3-chloro-2-hydroxy-benzylamine hydrochloride, m.p.177°-178° C (decomp.), of the formula ##STR31## crystallized out whenethyl acetate was added.

EXAMPLE 44

Using a procedure analogous to that described in Example 40,N-(trans-4'-hydroxy-cyclohexyl)-3,5-dichloro-2-hydroxy-benzylamine andits hydrochloride, m.p. 216°-222° C (decomp.), were prepared byreduction ofN-(3,5-dichloro-2-hydroxy-benzylidene)-trans-4'-amino-cyclohexanol withsodium borohydride.

EXAMPLE 45

Using a procedure analogous to that described in Example 40,N-(trans-4'-hydroxy-cyclohexyl)-3,5-dichloro-4-hydroxy-benzylamine andits hydrochloride, m.p. 222°-225° C (decomp.), were prepared byreduction ofN-(3,5-dichloro-4-hydroxy-benzylidene)-trans-4'-amino-cyclohexanol withsodium borohydride.

EXAMPLE 46

Using a procedure analogous to that described in Example 40,N-(trans-4'-hydroxy-cyclohexyl)-3-bromo-5-chloro-2-hydroxy-benzylamineand its hydrochloride, m.p. 214°-221° C (decomp.), were prepared byreduction ofN-(3-bromo-5-chloro-2-hydroxy-benzylidene)-trans-4'-amino-cyclohexanolwith sodium borohydride.

EXAMPLE 47

Using a procedure analogous to that described in Example 40,N-(trans-4'-hydroxy-cyclohexyl)-5-bromo-3-chloro-2-hydroxy-benzylamineand its hydrochloride, m.p. 193°-197° C (decomp.), were prepared byreduction ofN-(5-bromo-3-chloro-2-hydroxy-benzylidene)-trans-4'-amino-cyclohexanolwith sodium borohydride.

EXAMPLE 48

Using a procedure analogous to that described in Example 40,N-(trans-4'-hydroxy-cyclohexyl)-5-bromo-3-chloro-4-hydroxy-benzylamineand its hydrochloride, m.p. 220°-226° C (decomp.), were prepared byreduction ofN-(5-bromo-3-chloro-4-hydroxy-benzylidene)-trans-4'-amino-cyclohexanolwith sodium borohydride.

EXAMPLE 49

Using a procedure analogous to that described in Example 40,N-(trans-4'-hydroxy-cyclohexyl)-5-bromo-2-hydroxy-benzylamine and itshydrochloride, m.p. 222°-230° C (decomp.), were prepared by reduction ofN-(5-bromo-2-hydroxy-benzylidene)-trans-4'-amino-cyclohexanol withsodium borohydride.

EXAMPLE 50

Using a procedure analogous to that described in Example 39,N-(trans-4'-hydroxy-cyclohexyl)-2-bromo-5-hydroxy-benzylamine and itshydrochloride, m.p. 220°-225° C (decomp.), were prepared from2-bromo-5-hydroxy-benzyl bromide and trans-4'-amino-cyclohexanol.

EXAMPLE 51

Using a procedure analogous to that described in Example 40,N-(trans-4'-hydroxy-cyclohexyl)-3-bromo-4-hydroxy-benzylamine and itshydrochloride, m.p. 225°-227° C (decomp.), were prepared by reduction ofN-(3-bromo-4-hydroxy-benzylidene)-trans-4'-amino-cyclohexanol withsodium borohydride.

EXAMPLE 52

Using a procedure analogous to that described in Example 40,N-(trans-4'-hydroxy-cyclohexyl)-3-bromo-2-hydroxy-benzylamine and itshydrochloride, m.p. 194°-196° C (decomp.), were prepared by reduction ofN-(3-bromo-2-hydroxy-benzylidene)-trans-4'-amino-cyclohexanol withsodium borohydride.

EXAMPLE 53

Using a procedure analogous to that described in Example 40,N-(trans-4'-hydroxy-cyclohexyl)-2,6-dibromo-3-hydroxy-benzylamine andits hydrochloride, m.p. 269°-271° C (decomp.), were prepared byreduction ofN-(2,6-dibromo-3-hydroxy-benzylidene)-trans-4'-amino-cyclohexanol.

EXAMPLE 54

Using a procedure analogous to that described in Example 40,N-(cis-3'-hydroxy-cyclohexyl)-3,5-dichloro-2-hydroxy-benzylamine and itshydrochloride, m.p. 209°-214° C (decomp.), were prepared by reduction ofN-(3,5-dichloro-2-hydroxy-benzylidene)-cis-3'-amino-cyclohexanol.

EXAMPLE 55

Using a procedure analogous to that described in Example 40,N-(cis-3'-hydroxy-cyclohexyl)-3,5-dichloro-4-hydroxy-benzylamine and itshydrochloride, m.p. 219°-224° C (decomp.), were prepared by reduction ofN-(3,5-dichloro-4-hydroxy-benzylidene)-cis-3'-amino-cyclohexanol.

EXAMPLE 56

Using a procedure analogous to that described in Example 40,N-(cis-3'-hydroxy-cyclohexyl)-3-bromo-5-chloro-2-hydroxy-benzylamine andits hydrochloride, m.p. 197°-201° C (decomp.), were prepared byreduction ofN-(3-bromo-5-chloro-2-hydroxy-benzylidene)-cis-3'-amino-cyclohexanol.

EXAMPLE 57

Using a procedure analogous to that described in Example 40,N-(cis-3'-hydroxy-cyclohexyl)-5-bromo-3-chloro-2-hydroxy-benzylamine andits hydrochloride, m.p. 219°-222° C (decomp.), were prepared byreduction ofN-(5-bromo-3-chloro-2-hydroxy-benzylidene)-cis-3'-amino-cyclohexanol.

EXAMPLE 58

Using a procedure analogous to that described in Example 40,N-(cis-3'-hydroxy-cyclohexyl)-5-bromo-3-chloro-4-hydroxy-benzylamine andits hydrochloride, m.p. 216°-218° C (decomp.), were prepared byreduction ofN-(5-bromo-3-chloro-4-hydroxy-benzylidene)-cis-3'-amino-cyclohexanol.

EXAMPLE 59

Using a procedure analogous to that described in Example 40,N-(cis-3'-hydroxy-cyclohexyl)-5-bromo-2-hydroxy-benzylamine and itshydrochloride, m.p. 148°-151° C (decomp.), were prepared by reduction ofN-(5-bromo-2-hydroxy-benzylidene)-cis-3'-amino-cyclohexanol.

EXAMPLE 60

Using a procedure analogous to that described in Example 40,N-(cis-3'-hydroxy-cyclohexyl)-2-bromo-5-hydroxy-benzylamine and itshydrochloride, m.p. 245°-250° C (decomp.), were prepared by reduction ofN-(2-bromo-5-hydroxy-benzylidene)-cis-3'-amino-cyclohexanol.

EXAMPLE 61

Using a procedure analogous to that described in Example 40,N-(cis-3'-hydroxy-cyclohexyl)-2,4-dibromo-5-hydroxy-benzylamine and itshydrochloride, m.p. 278°-280° C (decomp.), were prepared by reduction ofN-(2,4-dibromo-5-hydroxy-benzylidene)-cis-3'-amino-cyclohexanol.

EXAMPLE 62

Using a procedure analogous to that described in Example 42,N-(cis-3'-hydroxy-cyclohexyl)-3-bromo-4-hydroxy-benzylamine and itshydrochloride, m.p. 214°-220° C (decomp.), were prepared by brominationof 4-hydroxy-N-(cis-3'-hydroxy-cyclohexyl)-benzylamine.

EXAMPLE 63

Using a procedure analogous to that described in Example 40,N-(cis-3'-hydroxy-cyclohexyl)-3-bromo-2-hydroxybenzylamine and itshydrochloride, m.p. 163°-167° C (decomp.), were prepared by reduction ofN-(3-bromo-2-hydroxy-benzylidene)-cis-3'-amino-cyclohexanol.

EXAMPLE 64

Using a procedure analogous to that described in Example 40,N-(cis-3'-hydroxy-cyclohexyl)-2,6-dibromo-3-hydroxy-benzylamine and itshydrochloride, m.p. 225°-259° C (decomp.), were prepared by reduction ofN-(2,6-dibromo-3-hydroxy-benzylidene)-cis-3'-amino-cyclohexanol.

EXAMPLE 65

Using a procedure analogous to that described in Example 42,N-ethyl-N-cyclohexyl-2-bromo-4-chloro-5-hydroxybenzylamine and itshydrochloride, m.p. 132.5°-137° C (decomp.), were prepared bybromination of N-ethyl-N-cyclohexyl-4-chloro-5-hydroxy-benzylamine.

EXAMPLE 66

Using a procedure analogous to that described in Example 39,N-ethyl-N-cyclohexyl-4-chloro-3-hydroxy-benzylamine and itshydrochloride, m.p. 128°-132° C (decomp.), were prepared from4-chloro-3-hydroxy-benzyl bromide and N-ethylcyclohexylamine.

EXAMPLE 67

Using a procedure analogous to that described in Example 39,N-ethyl-N-cyclohexyl-2-chloro-5-hydroxy-benzylamine and itshydrochloride, m.p. 210°-211° C, were prepared from2-chloro-5-hydroxy-benzyl bromide and N-ethyl-cyclohexyl-amine.

EXAMPLE 68

Using a procedure analogous to that described in Example 41,N-ethyl-N-cyclohexyl-2,4-dichloro-5-hydroxy-benzylamine and itshydrochloride, m.p. 179°-186° C (decomp.), were prepared by chlorinationof N-ethyl-N-cyclohexyl-5-hydroxybenzylamine.

EXAMPLE 69

Using a procedure analogous to that described in Example 43,N-ethyl-N-cyclohexyl-3-bromo-4-hydroxy-benzylamine and itshydrochloride, m.p. 185°-190° C (decomp.), were prepared from2-bromo-phenol, paraformaldehyde and N-ethylcyclohexylamine.

EXAMPLE 70

Using a procedure analogous to that described in Example 43,N-ethyl-N-cyclohexyl-4-chloro-2-hydroxy-benzylamine and itshydrochloride, m.p. 144°-146° C, were prepared from 3-chloro-phenol,paraformaldehyde and N-ethyl-cyclohexyl-amine.

EXAMPLE 71

Using a procedure analogous to that described in Example 43,N-ethyl-N-cyclohexyl-3-bromo-2-hydroxy-benzylamine and itshydrochloride, m.p. 171°-173° C, were prepared from 2-bromo-phenol,paraformaldehyde and N-ethyl-cyclohexylamine.

EXAMPLE 72

Using a procedure analogous to that described in Example 43,N-ethyl-N-cyclohexyl-4-bromo-2-hydroxy-benzylamine and itshydrochloride, m.p. 175°-177° C, were prepared from 3-bromo-phenol,paraformaldehyde and N-ethyl-cyclohexylamine.

EXAMPLE 73

Using a procedure analogous to that described in Example 41,N-ethyl-N-cyclohexyl-3-chloro-4-hydroxy-benzylamine and itshydrochloride, m.p. 181°-183° C, were prepared by chlorination ofN-ethyl-N-cyclohexyl-4-hydroxy-benzylamine.

EXAMPLE 74

Using a procedure analogous to that described in Example 43,N-ethyl-N-cyclohexyl-2-chloro-4-hydroxy-benzylamine and itshydrochloride, m.p. 165°-166.5° C, were prepared from 3-chloro-phenol,paraformaldehyde and N-ethyl-cyclohexyl-amine.

EXAMPLE 75

Using a procedure analogous to that described in Example 42,N-ethyl-N-cyclohexyl-(2-bromo-4-chloro-3-hydroxy)-benzylamine and itshydrochloride, m.p. 130°-137° C (decomp.), were prepared be brominationof N-ethyl-N-cyclohexyl-4-chloro-3-hydroxy-benzylamine.

EXAMPLE 76

Using a procedure analogous to that described in Example 42,N-ethyl-N-cyclohexyl-2,6-dibromo-3-hydroxy-benzylamine, m.p. 123°-126°C, was prepared by bromination ofN-ethyl-N-cyclohexyl-3-hydroxy-benzylamine.

EXAMPLE 77

Using a procedure analogous to that described in Example 41,N-ethyl-N-cyclohexyl-2,4-dichloro-3-hydroxy-benzylamine and itshydrochoride, m.p. 127°-132° C (decomp.), were prepared by chlorinationof N-ethyl-N-cyclohexyl-3-hydroxybenzylamine.

EXAMPLE 78 N-(Dihydroxy-tert.butyl)-3,5-dibromo-2-hydroxy-benzylamineand its hydrochloride by method A

21.6 gm of 3,5-dibromo-2-hydroxy-benzyl bromide dissolved in 0.5 literof carbon tetrachloride were admixed with a solution of 26.4 gm ofdihydroxy-tert.butylamine in 100 ml of ethanol and refluxed for 30minutes. The precipitate formed thereby was sucked off and washed withcarbon tetrachloride and water. The crude product was dissolved inabsolute ethanol and acidified with ethanolic hydrochloric acid, andN-(dihydroxy-tert.butyl)-3,5-dibromo-2-hydroxy-benzylaminehydrochloride, m.p. 187°-189° C, of the formula ##STR32## wascrystallized out by the addition of ether.

EXAMPLE 79 N-tert.pentyl-3,5-dibromo-2-hydroxy-benzylamine and itshydrochloride by method A

3.5 gm of 3,5-dibromo-2-hydroxy-benzyl alcohol and 1.4 gm of a sodiumhydride dispersion (50% in oil) were refluxed for 6 hours in 100 ml ofabsolute tetrahydrofuran. Subsequently, the reaction mixture was cooledto between -60° and -70° C, and 4.8 gm of p-toluene-sulfonic acidchloride in 50 ml of absolute tetrahydrofuran were added dropwise. Then,it was left standing until a temperature of -30° C was reached and wasagain cooled to -70° C. 4.4 gm of tert.pentylamine in 50 ml of etherwere added dropwise, while stirring, to the reaction mixture until itslowly reached room temperature. Subsequently, it was extracted twicewith water, the aqueous layer was extracted with chloroform, and thecombined organic phases were evaporated. After purification over acolumn of silicagel with chloroform/ethyl acetate (2:1),N-tert.pentyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride, m.p.202°-206° C (decomp.), of the formula ##STR33## was recrystallized fromacetone/ether after having been acidified with ethanolic hydrochloricacid and then recrystallized from water.

EXAMPLE 80 N-Isopropyl-3,5-dibromo-2-hydroxy-benzylamine and itshydrochloride by method C

16 gm of N-isopropylidene-3,5-dibromo-2-hydroxybenzylamine benzylaminein 120 ml of ethanol were admixed with 2 gm of sodium borohydride,stirred for 3 hours, then filtered, admixed with 40 ml of 2 N sodiumhydroxide and 200 ml of water, and evaporated to about half its volume.The solution was then admixed with saturated ammonium chloride solution,thus precipitating the crude base. The precipitate was sucked off andwashed intensely with water. The product was dissolved in acetone andacidified with ethanolic hydrochloric acid, whereuponN-isopropyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride, m.p.195°-199° C (decomp.), of the formula ##STR34## crystallized outimmediately.

EXAMPLE 81

Using a procedure analogous to that described in Example 78,N-isopropyl-3,5-dichloro-2-hydroxy-benzylamine and its hydrochloride,m.p. 188°-189.5° C, were prepared from 3,5-dichloro-2-hydroxy-benzylbromide and isopropylamine.

EXAMPLE 82

Using a procedure analogous to that described in Example 78,N-tert.butyl-3,5-dibromo-4-hydroxy-benzylamine and its hydrochloride,m.p. 234°-236° C (decomp.), of the formula ##STR35## were prepared from3,5-dibromo-4-hydroxy-benzyl bromide and tert.butylamine.

EXAMPLE 83

Using a procedure analogous to that described in Example 78,N-tert.butyl-3,5-dichloro-2-hydroxy-benzylamine, m.p. 172°-174° C wasprepared from 3,5-dichloro-2-hydroxybenzyl bromide and tert.butylamine.

EXAMPLE 84

Using a procedure analogous to that described in Example 78,N-tert.butyl-3,5-dichloro-4-hydroxy-benzylamine and its hydrochloride,m.p. 222°-223° C (decomp.), were prepared from3,5-dichloro-4-hydroxy-benzyl bromide and tert. butylamine.

EXAMPLE 85

Using a procedure analogous to that described in Example 78,N-tert.pentyl-3,5-dibromo-4-hydroxy-benzylamine and its hydrochloride,m.p. 176°-180° C (decomp.), were prepared from3,5-dibromo-4-hydroxy-benzyl bromide and tert. pentylamine.

EXAMPLE 86

Using a procedure analogous to that described in Example 78,N-tert.pentyl-3,5-dichloro-4-hydroxy-benzylamine and its hydrochloride,m.p. 203°-207° C (decomp.), were prepared from3,5-dichloro-4-hydroxy-benzyl bromide and tert. pentylamine.

EXAMPLE 87

Using a procedure analogous to that described in Example, 78,N-(hydroxy-tert.butyl)-3,5-dibromo-2-hydroxybenzylamine and itshydrochloride, m.p. 189°-191° C, were prepared from3,5-dibromo-2-hydroxy-benzyl bromide and hydroxytert.butylamine.

EXAMPLE 88

Using a procedure analogous to that described in Example 78,N-(hydroxy-tert.butyl)-3,5-dibromo-4-hydroxybenzylamine and itshydrochloride, m.p. 200°-202° C, were prepared from3,5-dibromo-4-hydroxy-benzyl bromide and hydroxytert.butylamine.

EXAMPLE 89

Using a procedure analogous to that described in Example 78,N-(hydroxy-tert.butyl)-3,5-dichloro-4-hydroxybenzylamine and itshydrochloride, m.p. 208°-212° C (decomp.), were prepared from3,5-dichloro-4-hydroxy-benzyl bromide and hydroxy-tert.butylamine.

EXAMPLE 90

Using a procedure analogous to that described in Example 78,N-(dihydroxy-tert.butyl)-3,5-dibromo-4-hydroxybenzylamine and itshydrochloride, m.p. 182°-183.5° C, were prepared from3,5-dibromo-4-hydroxy-benzyl bromide and dihydroxy-tert.butylamine.

EXAMPLE 91

Using a procedure analogous to that described in Example 78,N-(trihydroxy-tert.butyl)-3,5-dibromo-4-hydroxybenzylamine and itshydrochloride, m.p. 189-191.5° C, were prepared from3,5-dibromo-4-hydroxy-benzyl bromide and trihydroxy-tert.butylamine.

EXAMPLE 92

Using a procedure analogous to that described in Example 78,N-(dihydroxy-tert.butyl)-3,5-dichloro-4-hydroxybenzylamine and itshydrochloride, m.p. 166°-169° C (decomp.), were prepared from3,5-dichloro-4-hydroxy-benzyl bromide and dihydroxy-tert.butylamine.

EXAMPLE 93

Using a procedure analogous to that described in Example 78,N-(trihydroxy-tert.butyl)-3,5-dibromo-2-hydroxybenzylamine and itshydrochloride, m.p. 185°-187° C (decomp.), were prepared from3,5-dibromo-2-hydroxy-benzyl bromide and trihydroxy-tert.butylamine.

EXAMPLE 94

Using a procedure analogous to that described in Example 78,N-(trihydroxy-tert.butyl)-3,5-dichloro-4-hydroxy-benzylamine and itshydrochloride, m.p. 170°-174° C (decomp.), were prepared from3,5-dichloro-4-hydroxy-benzyl bromide and trihydroxy-tert.butylamine.

EXAMPLE 95 N-tert.butyl-3,5-dibromo-2-hydroxy-benzylamine and itshydrochloride by method B

7 gm of 3,5-dibromo-salicylaldehyde, 17.5 gm of tert. butylamine and 7.7gm of formic acid were heated for 6 hours at 70°-80° C. Subsequently,the reaction mixture was admixed with aqueous 2 N ammonia, vigorouslyshaken, and the precipitate formed thereby was sucked off. The residuewas dissolved in ethanol, acidified with ethanolic hydrochloric acid andadmixed with ether in order to crystallize the product out.N-tert.butyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride, m.p.216°-220° C (decomp.), was obtained after recrystallization fromabsolute ethanol/ether.

EXAMPLE 96 N-isopropyl-3,5-dibromo-4-hydroxy-benzylamine and itshydrochloride by method C

7.3 gm of N-(3,5-dibromo-4-hydroxy-benzylidene)-isopropylamine werestirred for 2 hours together with 1 gm of sodium borohydride in 200 mlof ethanol. Some acetone was added to the reaction mixture in order todecompose the excess sodium borohydride; then, it was acidified with 2 Nhydrochloric acid and evaporated to a small volume. After addition of 2N ammonia to alkaline reaction, the yellowish precipitate was suckedoff. The residue was dissolved in absolute ethanol and acidified withethanolic hydrochloric acid. Ether was added to crystallize outN-isopropyl-3,5-dibromo-4-hydroxy-benzylamine hydrochloride, m.p.229°-233° C (decomp.).

EXAMPLE 97

Using a procedure analogous to that described in Example 96,N-isopropyl-3,5-dichloro-4-hydroxy-benzylamine and its hydrochloride,m.p. 223°-231° C (decomp.), were prepared by reduction ofN-(3,5-dichloro-4-hydroxy-benzylidene)-isopropylamine.

EXAMPLE 98

Using a procedure analogous to that described in Example 96,N-tert.pentyl-3,5-dichloro-2-hydroxy-benzylamine and its hydrochloride,m.p. 211°-213° C (decomp.), were prepared by reduction ofN-(3,5-dichloro-2-hydroxy-benzylidene)-tert.pentylamine.

EXAMPLE 99

Using a procedure analogous to that described in Example 96,N-(hydroxy-tert.butyl)-3,5-dichloro-2-hydroxybenzylamine and itshydrochloride, m.p. 200°-204.5° C (decomp.), were prepared by reductionof N-(3,5-dichloro-2-hydroxy-benzylidene)-hydroxy-tert.butylamine.

EXAMPLE 100

Using a procedure analogous to that described in Example 96,N-(dihydroxy-tert.butyl)-3,5-dichloro-2-hydroxybenzylamine and itshydrochloride, m.p. 184°-188° C (decomp.), were prepared by reduction ofN-(3,5-dichloro-2-hydroxybenzylidene)-dihydroxy-tert.butylamine.

EXAMPLE 101

Using a procedure analogous to that described in Example 96,N-(trihydroxy-tert.butyl)-3,5-dichloro-2-hydroxybenzylamine and itshydrochloride, m.p. 172°-176° C (decomp.), were prepared by reduction ofN-(3,5-dichloro-2-hydroxybenzylidene)-trihydroxy-tert.butylamine.

EXAMPLE 102

Using a procedure analogous to that described in Example 96,N-tert.butyl-5-bromo-2-hydroxy-benzylamine and its hydrochloride, m.p.255°-258° C (decomp.), were prepared by reduction ofN-(5-bromo-2-hydroxy-benzylidene)-tert.butylamine.

The compounds according to the present invention, that is, thoseembraced by formula I above and their nontoxic, pharmacologicallyacceptable acid addition salts, have useful pharmacodynamic properties.More particularly, the compounds of the present invention exhibit a veryeffective stimulating action on the production of the surfactant orantiatelectasis factor of the alveoli, secretolytic activity,anti-ulcerogenic activity and antitussive activity in warm-bloodedanimals, such as rats, guinea pigs, cats, rabbits and mice.

The above-indicated pharmacological activities were ascertained for thecompounds of the present invention by the methods described below, andthe following are the results obtained for a few representativecompounds, where

A = n-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylaminehydrochloride,

B = n-ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylaminehydrochloride,

C = n-(cis-3'-hydroxy-cyclohexyl)-3,5-dibromo-4-hydroxybenzylaminehydrochloride,

D = n-(trans-4'-hydroxy-cyclohexyl)-3-bromo-2-hydroxybenzylaminehydrochloride,

E = n-methyl-N-cyclohexyl-3-bromo-5-chloro-4-hydroxy-benzylaminehydrochloride,

F = n-(trans-4'-hydroxy-cyclohexyl)-3,5-dibromo-2-hydroxybenzylaminehydrochloride,

G = n-(dihydroxy-tert.butyl)-3,5-dibromo-2-hydroxy-benzylaminehydrochloride, H =N-(dihydroxy-tert.butyl)-3,5-dichloro-4-hydroxy-benzylaminehydrochloride,

I = n-tert.pentyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride, and

J = n-methyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylaminehydrochloride.

1. Antitussive Activity

50 mgm/kg of the test compound were administered orally to each animalof a group of 10 awake white rats. These rats were made to cough by aspray of an aqueous solution containing 7.5% citric acid. 30 minutesafter the application of the test compound the average change in thenumber of coughs was determined in percent, compared to a control groupof 10 animals see Engelhorn and Puschmann in Arzneimittelforschung 13,474-480 (1963)!.

                  TABLE I    ______________________________________             Average change in the number of coughs, in             per cent, 30 minutes after oral application    Compound of 50 mgm/kg    ______________________________________    A        -38    B        -34    C        -35    ______________________________________

2. Expectorant Effect

The secretolytic activity was tested on 8 to 10 anesthetized rabbits or5 anesthetized guinea pigs after oral application of 8 mgm/kg of thetest compound. The increase of secretion within 2 hours was calculatedbefore and after application of the substance see Perry and Boyd inPharmakol. exp. Therap. 73, 65 (1941)!.

The circulatory effect in cats was determined under chloralose-urethanenarcosis after intravenous application of the test compound (3 animalsper dose).

                  TABLE II    ______________________________________             Increase of    Compound secretion  Circulatory effect in cats    ______________________________________    A        +81%       4 mgm/kg:  no change                        8 mgm/kg:  slight fall of                                   blood-pressure for                                   a short time    B        +87%       8 mgm/kg:  no change    ______________________________________

                  TABLE III    ______________________________________    Compound      Increase of secretion    ______________________________________    D             +66%    E             +65%    F             +70%    G             +88%    H             +88%    I             +80%    ______________________________________

3. Anti-ulcerogenic activity

The standard pharmacological test method of K. Tagaki et al, Jap. J.Pharmac. 19, 418 (1969), was used. The abdominal cavity of female ratshaving a body weight of 220 to 350 gm under ether anesthesia was opened,and the stomach was exposed. Thereafter, 0.05 ml of an aqueous 5%solution of acetic acid was injected in one location between themuscularis mucosae and the submucosa of the stomach of each animal, andthe abdominal cavity was closed again. 3 to 5 days after this injectionthe animals developed stomach ulcers in the mucous membrane at the locusof injection, whereupon the animals were treated over a period of threeweeks by adding the test compound at dosage levels of 50 and 100 mgm/kgto their daily food ration, using 5 to 8 animals per dose. The controlsreceived only pulverized rat food. After three weeks, the animals weresacrificed, their stomachs were excised, and the size of the ulcer wasdetermined by measuring its length and width. The anti-ulcerogeniceffect of the test compound was expressed in terms of average percentdifference in size of the treated ulcers over the controls (100%).

The following table shows the results obtained from these tests:

                  TABLE IV    ______________________________________             Dose in mgm/kg                          % Reduction in ulcer size    Compound p.o.         over controls    ______________________________________    Controls powdered food                            0    J        50           -73             100          -82    F        50           -59             100          -78    A        50           -39             100          -54    C        50           -11             100          -29    ______________________________________

4. Acute Toxicity

The acute toxicity was determined on groups of 5 white mice after oralapplication of a dose ranging between 500 mgm/kg and 5000 mgm/kg peranimal (time of observation: 72 hours).

                  TABLE V    ______________________________________    Compound Acute Toxicity    ______________________________________    A        >1000 mgm/kg, p.o. (0 of 5 animals dead)    B        >1000 mgm/kg, p.o. (0 of 5 animals dead)    C        >1000 mgm/kg, p.o. (0 of 5 animals dead)    D        > 500 mgm/kg, p.o (0 of 5 animals dead)    E        > 500 mgm/kg, p.o. (0 of 5 animals dead)    F        >5000 mgm/kg, p.o. (0 of 5 animals dead)    G        >5000 mgm/kg, p.o. (0 of 5 animals dead)    H        --    I        >5000 mgm/kg, p.o. (0 of 5 animals dead)    J        >5000 mgm/kg, p.o. (1 of 5 animals dead)    ______________________________________

For pharmaceutical use as secretolytics, antitussives and stimulants ofthe anti-atelectasis factor, the compounds of the present invention areadministered to warm-blooded animals, perorally, parenterally orrectally as active ingredients in customary pharmaceutical compositions,that is, compositions consisting essentially of an inert pharmaceuticalcarrier and an effective amount of the active ingredient, such astablets, coated pills, capsules, wafers, powders, solutions,suspensions, emulsions, syrups, suppositories, tinctures, ointments,aerosols and the like. The single effective dose for these purposes isabout 0.017 to 0.333 mgm/kg, preferably 0.033 to 0.167 mgm/kg bodyweight.

For pharmaceutical use as anti-ulcerogenics, the compounds of theformula I or their non-toxic acid addition salts are administered towarm-blooded animals perorally as active ingredients in customary oraldosage unit compositions, that is, compositions in dosage unit formconsisting essentially of an inert pharmaceutical carrier and oneeffective anti-ulcerogenic dosage unit of the active ingredient, such astablets, coated pills, capsules, wafers, powders, solutions,suspensions, emulsions, syrups and the like. The effectiveanti-ulcerogenic oral single dosage unit of the compounds is from 0.42to 1.67 mgm/kg body weight, preferably 0.5 to 1.0 mgm/kg body weight.The daily dose rate, administered in three to four single doses, is from1.25 to 6.7 mgm/kg body weight, preferably 1.5 to 4.0 mgm/kg bodyweight.

The following examples illustrate a few pharmaceutical compositionscomprising a compound of the present invention as an active ingredientand represent the best modes contemplated of putting the invention intopractical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 103

    ______________________________________    Syrup    The syrup was compounded from the following    ingredients:    N-Ethyl-N-cyclohexyl-3,5-dibromo-4-    hydroxy-benzylamine hydrochloride                          0.04      parts    Tartaric acid         0.50      parts    Benzoic acid          0.20      parts    Ammonium chloride     0.40      parts    Glycerin              10.00     parts    Sorbitol              50.00     parts    Naphthol Red S        0.01      parts    Flavoring             0.25      parts    Ethanol               10.00     parts    Distilled waterq.s.ad 100.00    parts                                    by vol.    ______________________________________

Preparation:

45 gm of the distilled water were warmed to 80° C. Then the tartaricacid, the benzoic acid, the benzylamine, the naphthol and the sorbitolwere successively dissolved in the water which was subsequently mixedwith the glycerin and an aqueous 20% solution of ammonium chloride.After cooling to room temperature, the ethanol and the flavoring werestirred into the mixture. The syrup was diluted to the indicated volumewith distilled water and filtered. Each 10 ml portion of the syrupcontained 4 mgm of the benzylamine hydrochloride, and was an oral dosageunit composition with very effective secretolytic and antitussiveaction, as well as a stimulant effect upon the production of thesurfactant or anti-atelectasis factor of the alveoli.

EXAMPLE 104 Drop Solution

The solution was compounded from the following ingredients:

    ______________________________________    N-Ethyl-N-cyclohexyl-3,5-dibromo-4-    hydroxy-benzylamine hydrochloride                          0.40      parts    p-Hydroxy-benzoic acid methyl ester                          0.07      parts    p-Hydroxy-benzoic acid propyl ester                          0.03      parts    Polyvinylpyrrolidone  5.00      parts    Anise oil             0.01      parts    Fennel oil            0.001     parts    Ethanol               10.00     parts    Distilled waterq.s.ad 100.00    parts                                    by vol.    ______________________________________

Preparation:

The p-hydroxy-benzoic acid esters, the polyvinylpyrrolidone and thebenzylamine salt were successively dissolved in the distilled waterwarmed to 80° C. The solution was cooled and subsequently mixed with themixture of the aromatic oils and the ethanol. The solution was dilutedto the indicated volume with distilled water and filtered. Each ml ofdrop solution contained 4 mgm of the benzylamine hydrochloride, and wasan oral dosage unit composition with very effective secretolytic andantitussive action, as well as a stimulant effect upon the production ofthe surfactant or anti-atelectasis factor of the alveoli.

EXAMPLE 105 Tablets

The tablet composition was compounded from the following ingredients:

    ______________________________________    N-Ethyl-N-cyclohexyl-3,5-dibromo-4-    hydroxy-benzylamine hydrochloride                          4.0       parts    Lactose               60.0      parts    Potato starch         41.0      parts    Polyvinylpyrrolidone  4.0       parts    Magnesium stearate    1.0       parts    Total                 110.0     parts    ______________________________________

Preparation:

The benzylamine salt was admixed with the lactose and the potato starchand granulated through a screen of 1 mm mesh-size with an aqueous 20%solution of the polyvinylpyrrolidone. The moist granulate was dried at40° C, again passed through the above mentioned screen and admixed withthe magnesium stearate. The mixture was compressed into 110 mgm-tablets.Each tablet contained 4 mgm of the benzylamine salt and was an oraldosage unit composition with very effective secretolytic and antitussiveaction, as well as a stimulant action upon the production of thesurfactant or anti-atelectasis factor of the alveoli.

EXAMPLE 106 Coated Pills

The pill core composition was compounded from the following ingredients:

    ______________________________________    N-Ethyl-N-cyclohexyl-3,5-dibromo-4-    hydroxy-benzylamine hydrochloride                          4.0       parts    Lactose               60.0      parts    Potato starch         41.0      parts    Polyvinylpyrrolidone  4.0       parts    Magnesium stearate    1.0       parts    Total                 110.0     parts    ______________________________________

Preparation:

The benzylamine salt was admixed with the lactose and the potato starchand granulated through a screen of 1 mm mesh-size with an aqueous 20%solution of the polyvinylpyrrolidone. The moist granulate was dried at40° C, again passed through the above mentioned screen and admixed withthe magnesium stearate. The mixture was compressed into 110 mgm-pillcores, which were coated in conventional manner with a thin shellconsisting essentially of sugar and talcum, and were then polished withbeeswax. Each coated pill contained 4 mgm of the benzylamine salt andwas an oral dosage unit composition with very effective secretolytic andantitussive action, as well as a stimulant effect upon the production ofthe surfactant or anti-atelectasis factor of the alveoli.

EXAMPLE 107 Suppositories

The suppository composition was compounded from the followingingredients:

    ______________________________________    N-Ethyl-N-cyclohexyl-3,5-dibromo-4-    hydroxy-benzylamine hydrochloride                          4.0       parts    Suppository base (cocoa butter)                          1696.0    parts    Total                 1700.0    parts    ______________________________________

Preparation:

The finely pulverized benzylamine salt was stirred into the moltensuppository base which had been cooled to 40° C and the mixture washomogenized. The mixture was then poured at about 35° C into cooledsuppository molds. Each suppository contained 4 mgm of the benzylaminesalt and was a rectal dosage unit composition with very effectivesecretolytic and antitussive action, as well as a stimulant effect uponthe production of the surfactant or anti-atelectasis factor of thealveoli.

EXAMPLE 108 Hypodermic solution

The solution was compounded from the following ingredients:

    ______________________________________    N-Ethyl-N-cyclohexyl-3,5-dibromo-4-    hydroxy-benzylamine hydrochloride                          4.0       parts    Tartaric acid         2.0       parts    Glucose               95.0      parts    Distilled waterq.s.ad 2000.0    parts                                    by vol.    ______________________________________

Preparation:

Some of the distilled water was warmed to 80° C, and the tartaric acidand the benzylamine salt were dissolved therein while stirring. Aftercooling to room temperature, the glucose was dissolved therein, and thesolution was filled into white 2 ml-ampules under aseptic conditions.The filled ampules were then sterilized at 120° C for 20 minutes andsealed. Each ampule contained 4 mgm of the benzylamine salt and was aninjectable parenteral dosage unit composition with very effectivesecretolytic and antitussive action, as well as a stimulant effect uponthe production of the surfactant or anti-atelectasis factor of thealveoli.

EXAMPLE 109 Tablets

The tablet composition was compounded from the following ingredients:

    ______________________________________    N-Cyclohexyl-N-methyl-3,5-dibromo-2-    hydroxy-benzylamine hydrochloride                          50.0      parts    Sec. calcium phosphate, anhydrous                          120.0     parts    Colloidal silicic acid                          10.0      parts    Corn starch           30.0      parts    Polyvinylpyrrolidone  5.0       parts    Potato starch         20.0      parts    Maleic acid           3.0       parts    Magnesium stearate    2.0       parts    Total                 240.0     parts    ______________________________________

Preparation:

The benzylamine salt, the calcium phosphate, the colloidal silicic acidand the corn starch are intimately admixed with each other, the mixtureis moistened with an ethanolic 10% solution of the polyvinylpyrrolidonecontaining the maleic acid, the moist mass is granulated through a 1.5mm-mesh screen, and the granulate is dried at 45° C and again passedthrough the screen. The granulate is then admixed with the potato starchand the magnesium stearate, and the resulting composition is compressedinto 240 mgm-tablets in a conventional tablet making machine. Eachtablet contains 50 mgm of the benzylamine salt and is an oral dosageunit composition with effective anti-ulcerogenic action.

EXAMPLE 110 Coated pills

The pill core composition is compounded from the following ingredients:

    ______________________________________    3,5-Dibromo-2-hydroxy-N-(trans-4-hydroxy    cyclohexyl)-benzylamine hydrochloride                           30.0      parts    Sec. calcium phosphate, anhydrous                           100.0     parts    Colloidal silicic acid 10.0      parts    Corn starch            20.0      parts    Polyvinylpyrrolidone   5.0       parts    Potato starch          10.0      parts    Maleic acid            3.0       parts    Magnesium stearate     2.0       parts    Total                  180.0     parts    ______________________________________

Preparation:

The ingredients are compounded as described in Example 109, and thecomposition is compressed into 180 mgm-pill cores which are subsequentlycoated with a thin shell consisting essentially of a mixture of sugarand talcum. Each coated pill contains 30 mgm of the benzylamine salt andis an oral dosage unit composition with effective anti-ulcerogenicaction.

EXAMPLE 111 Gelatin capsules

The capsule filler composition is compounded from the followingingredients:

    ______________________________________    N-Ethyl-N-cyclohexyl-3,5-dibromo-2-    hydroxy-benzylamine hydrochloride                          50.0      parts    Potato starch         40.0      parts    Talcum                10.0      parts    Total                 100.0     parts    ______________________________________

Preparation:

The ingredients are intimately admixed with each other, and 100mgm-portions of the mixture are filled into gelatin capsules of suitablesize. Each capsule contains 50 mgm of the benzylamine salt and is anoral dosage unit composition with effective anti-ulcerogenic action.

EXAMPLE 112 Solution

The solution is compounded from the following ingredients:

    ______________________________________    3,5-Dibromo-4-hydroxy-N-(cis-3-hydroxy-    cyclohexyl)-benzylamine hydrochloride                          0.5      parts    Sugar                 70.0     parts    Tartaric acid         0.3      parts    Sec. sodium phosphate . 2 H.sub.2 O                          1.2      parts    Saccharin sodium      0.2      parts    Methyl p-hydroxy-benzoate                          0.07     parts    Propyl p-hydroxy-benzoate                          0.03     parts    Essence of eucalyptus-menthol                          0.2      parts    Raspberry flavoring   0.02     parts    Ethanol, pure         2.0      parts    Distilled waterq.s.ad 100.0    parts                                   by vol    ______________________________________

Preparation:

About 50 ml of distilled water are heated to 80° C, and thep-hydroxybenzoates, the sugar, the saccharin sodium, the tartaric acid,the secondary sodium phosphate and the benzylamine salt are dissolvedtherein. Then, a solution of the essence of eucalyptus-menthol and theraspberry flavoring in the ethanol is stirred in. Subsequently thesolution is diluted with distilled water to the indicated volume andfiltered until clear. 10 ml of the solution contain 50 mgm of thebenzylamine salt and are an oral dosage unit composition with effectiveanti-ulcerogenic action.

Analogous results are obtained when any one of the other benzylaminesembraced by formula I or a non-toxic, pharmacologically acceptable acidaddition salt thereof is substituted for the particular benzylamine saltin Examples 103 through 112. Likewise, the amount of active ingredientin these illustrative examples may be varied to achieve the respectivedosage unit ranges set forth above, and the amounts and nature of theinert pharmaceutical carrier ingredients may be varied to meetparticular requirements.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to these particularembodiments, and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappended claims.

We claim:
 1. A secretolytic pharmaceutical dosage unit compositionconsisting essentially of an inert pharmaceutical carrier and aneffective secretolytic amount of a compound of the formula ##STR36##wherein X is chlorine or bromine;R₁ is hydrogen, chlorine or bromine; R₂is isopropyl; tert.butyl; tert.pentyl; mono-, di ortri-hydroxy-substituted branched alkyl of 3 to 5 carbon atoms;cyclohexyl; or hydroxycyclohexyl; and R₃ is alkyl of 1 to 4 carbon atomsor, when R₂ is other than cyclohexyl, also hydrogen;or a non-toxic,pharmacologically acceptable acid addition salt thereof.
 2. The methodof stimulating the secretion of respiratory fluids in a warm-bloodedanimal, which comprises perorally, parenterally or rectallyadministering to said animal an effective secretolytic amount of acompound of the formula ##STR37## wherein X is chlorine or bromine;R₁ ishydrogen, chlorine or bromine; R₂ is isopropyl; tert.butyl; tert.pentyl;mono-, di- or tri-hydroxy-substituted branched alkyl of 3 to 5 carbonatoms; cyclohexyl; or hydroxycyclohexyl; and R₃ is alkyl of 1 to 4carbon atoms or, when R₂ is other than cyclohexyl, also hydrogen; or anon-toxic, pharmacologically acceptable acid addition salt thereof.